Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, mini-brain tissues called organoids have been derived from human induced pluripotent stem cells (hiPSCs) for modeling human brain development and neurological diseases. Thus, the objective of this research is to model and characterize neural degeneration microenvironment using three-dimensional (3D) forebrain cortical organoids derived from hiPSCs and study the response to the drug treatment. It is hypothesized that the 3D forebrain organoids derived from hiPSCs with AD-associated genetic background may partially recapitulate the extracellular microenvironment in neural degeneration. To test this hypothesis, AD-patient derived hiPSCs with presenilin-1 mutation were used for cortical organoid generation. AD-related inflammatory responses, matrix remodeling and the responses to DAPT, heparin (completes with heparan sulfate proteoglycans [HSPGs] to bind Aβ42), and heparinase (digests HSPGs) treatments were investigated. The results indicate that the cortical organoids derived from AD-associated hiPSCs exhibit a high level of Aβ42 comparing with healthy control. In addition, the AD-derived organoids result in an elevated gene expression of proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, upregulate syndecan-3, and alter matrix remodeling protein expression. Our study demonstrates the capacity of hiPSC-derived organoids for modeling the changes of extracellular microenvironment and provides a potential approach for AD-related drug screening.
Get full access to this article
View all access options for this article.
References
1.
LancasterM.A., RennerM., MartinC.A., et al.Cerebral organoids model human brain development and microcephaly. Nature, 501, 373, 2013.
2.
PascaA.M., SloanS.A., ClarkeL.E., et al.Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods, 12, 671, 2015.
3.
MarianiJ., SimoniniM.V., PalejevD., et al.Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci U S A, 109, 12770, 2012.
4.
van den AmeeleJ., TiberiL., VanderhaeghenP., and Espuny-CamachoI.Thinking out of the dish: what to learn about cortical development using pluripotent stem cells. Trends Neurosci, 37, 334, 2014.
5.
EirakuM., WatanabeK., Matsuo-TakasakiM., et al.Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell, 3, 519, 2008.
6.
Marti-FigueroaC.R., and AshtonR.S.The case for applying tissue engineering methodologies to instruct human organoid morphogenesis. Acta Biomater, 54, 35, 2017.
7.
ShahS.B., and SinghA.Cellular self-assembly and biomaterials-based organoid models of development and diseases. Acta Biomater, 53, 29, 2017.
8.
Di LulloE., and KriegsteinA.R.The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci, 18, 573, 2017.
9.
ChoiS.H., KimY.H., HebischM., et al.A three-dimensional human neural cell culture model of Alzheimer's disease. Nature, 515, 274, 2014.
10.
ZhangD., Pekkanen-MattilaM., ShahsavaniM., FalkA., TeixeiraA.I., and HerlandA.A 3D Alzheimer's disease culture model and the induction of P21-activated kinase mediated sensing in iPSC derived neurons. Biomaterials, 35, 1420, 2014.
11.
LeeH.K., Velazquez SanchezC., ChenM., et al.Three dimensional human neuro-spheroid model of Alzheimer's disease based on differentiated induced pluripotent stem cells. PLoS One, 11, e0163072, 2016.
12.
LiY., MuffatJ., OmerA., et al.Induction of expansion and folding in human cerebral organoids. Cell Stem Cell, 20, 385, 2017.
13.
PistollatoF., OhayonE.L., LamA., et al.Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities. Oncotarget, 7, 38999, 2016.
14.
RajaW.K., MungenastA.E., LinY.T., et al.Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer's disease phenotypes. PLoS One, 11, e0161969, 2016.
15.
VazinT., BallK.A., LuH., et al.Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer's disease. Neurobiol Dis, 62, 62, 2014.
16.
KondoT., AsaiM., TsukitaK., et al.Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell, 12, 487, 2013.
17.
ChoiY.J., ParkJ., and LeeS.H.Size-controllable networked neurospheres as a 3D neuronal tissue model for Alzheimer's disease studies. Biomaterials, 34, 2938, 2013.
18.
NiewegK., AndreyevaA., van StegenB., TanrioverG., and GottmannK.Alzheimer's disease-related amyloid-beta induces synaptotoxicity in human iPS cell-derived neurons. Cell Death Dis, 6, e1709, 2015.
19.
IsraelM.A., YuanS.H., BardyC., et al.Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature, 482, 216, 2012.
20.
GoldsteinL.S., ReynaS., and WoodruffG.Probing the secrets of Alzheimer's disease using human-induced pluripotent stem cell technology. Neurotherapeutics, 12, 121, 2015.
21.
YangJ., ZhaoH., MaY., et al.Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations. Oncotarget, 8, 7900, 2017.
22.
KanekiyoT., ZhangJ., LiuQ., LiuC.C., ZhangL., and BuG.Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake. J Neurosci, 31, 1644, 2011.
23.
LiuC.C., ZhaoN., YamaguchiY., et al.Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-beta clearance and aggregation in Alzheimer's disease. Sci Transl Med, 8, 332ra44, 2016.
24.
Si-TayebK., NotoF.K., SepacA., et al.Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev Biol, 10, 81, 2010.
25.
Si-TayebK., NotoF.K., NagaokaM., et al.Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology, 51, 297, 2010.
26.
YanY., MartinL., BoscoD., et al.Differential effects of acellular embryonic matrices on pluripotent stem cell expansion and neural differentiation. Biomaterials, 73, 231, 2015.
27.
BejoyJ., SongL., ZhouY., and LiY.Wnt-YAP interactions during neural tissue patterning of human induced pluripotent stem cells. Tissue Eng Part A, 2017. [Epub ahead of print]; DOI:10.1089/ten.TEA.2017.0153.
28.
YanY., BejoyJ., XiaJ., GuanJ., ZhouY., and LiY.Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses. Acta Biomater, 42, 114, 2016.
29.
YanY., SongL., MadinyaJ., MaT., and LiY.Derivation of cortical spheroids from human induced pluripotent stem cells in a suspension bioreactor. Tissue Eng Part A. 2017 [Epub ahead of print]; DOI:10.1089/ten.TEA.2016.0400.
30.
SongL., TsaiA.C., YuanX., et al.Neural differentiation of spheroids derived from hiPSC-MSC co-culture. Tissue Eng Part A. 2017 [Epub ahead of print]; DOI:10.1089/ten.TEA.2017.0403.
31.
YanY., LiY., SongL., ZengC., and LiY.Pluripotent stem cell expansion and neural differentiation in 3-D scaffolds of tunable Poisson's ratio. Acta Biomater, 49, 192, 2017.
32.
SartS., YanY., LiY., et al.Crosslinking of extracellular matrix scaffolds derived from pluripotent stem cell aggregates modulates neural differentiation. Acta Biomater, 30, 222, 2016.
33.
WrenM.C., ZhaoJ., LiuC.C., et al.Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells. Mol Neurodegener, 10, 46, 2015.
34.
ZhaoJ., DavisM.D., MartensY.A., et al.APOE epsilon4/epsilon4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum Mol Genet, 26, 2690, 2017.
35.
MarshS.E., AbudE.M., LakatosA., et al.The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A, 113, E1316, 2016.
36.
HeppnerF.L., RansohoffR.M., and BecherB.Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci, 16, 358, 2015.
37.
BespalovM.M., SidorovaY.A., TumovaS., et al.Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin. J Cell Biol, 192, 153, 2011.
38.
BergamaschiniL., DonariniC., RossiE., De LuigiA., VerganiC., and De SimoniM.G.Heparin attenuates cytotoxic and inflammatory activity of Alzheimer amyloid-beta in vitro. Neurobiol Aging, 23, 531, 2002.
39.
QianX., NguyenH.N., SongM.M., et al.Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell, 165, 1238, 2016.
40.
OvchinnikovD.A., and WolvetangE.J.Opportunities and limitations of modelling Alzheimer's disease with induced pluripotent stem cells. J Clin Med, 3, 1357, 2014.
41.
YagiT., ItoD., OkadaY., et al.Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet, 20, 4530, 2011.
42.
MuratoreC.R., RiceH.C., SrikanthP., et al.The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet, 23, 3523, 2014.
ZhengW.H., BastianettoS., MennickenF., MaW., and KarS.Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience, 115, 201, 2002.
45.
LaFerlaF.M.Pathways linking Abeta and tau pathologies. Biochem Soc Trans, 38, 993, 2010.
46.
BaiB., HalesC.M., ChenP.C., et al.U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease. Proc Natl Acad Sci U S A, 110, 16562, 2013.
47.
ChakrabartyP., Jansen-WestK., BeccardA., et al.Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J, 24, 548, 2010.
48.
HeyserC.J., MasliahE., SamimiA., CampbellI.L., and GoldL.H.Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. Proc Natl Acad Sci U S A, 94, 1500, 1997.
49.
PerryR.T., CollinsJ.S., WienerH., ActonR., and GoR.C.The role of TNF and its receptors in Alzheimer's disease. Neurobiol Aging, 22, 873, 2001.
50.
ProkopS., MillerK.R., and HeppnerF.L.Microglia actions in Alzheimer's disease. Acta Neuropathol, 126, 461, 2013.
51.
LauL.W., CuaR., KeoughM.B., Haylock-JacobsS., and YongV.W.Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat Rev Neurosci, 14, 722, 2013.
52.
HenekaM.T., CarsonM.J., El KhouryJ., et al.Neuroinflammation in Alzheimer's disease. Lancet Neurol, 14, 388, 2015.
53.
HenekaM.T., GolenbockD.T., and LatzE.Innate immunity in Alzheimer's disease. Nat Immunol, 16, 229, 2015.
54.
BrkicM., BalusuS., LibertC., and VandenbrouckeR.E.Friends or foes: matrix metalloproteinases and their multifaceted roles in neurodegenerative diseases. Mediators Inflamm, 2015, 620581, 2015.
55.
LepelletierF.X., MannD.M., RobinsonA.C., PinteauxE., and BoutinH.Early changes in extracellular matrix in Alzheimer's disease. Neuropathol Appl Neurobiol, 43, 167, 2017.
56.
LiW., PoteetE., XieL., LiuR., WenY., and YangS.H.Regulation of matrix metalloproteinase 2 by oligomeric amyloid beta protein. Brain Res, 1387, 141, 2011.
57.
MeighanS.E., MeighanP.C., ChoudhuryP., et al.Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J Neurochem, 96, 1227, 2006.
58.
MlekuschR., and HumpelC.Matrix metalloproteinases-2 and −3 are reduced in cerebrospinal fluid with low beta-amyloid1-42 levels. Neurosci Lett, 466, 135, 2009.
59.
van HorssenJ., WesselingP., van den HeuvelL.P., de WaalR.M., and VerbeekM.M.Heparan sulphate proteoglycans in Alzheimer's disease and amyloid-related disorders. Lancet Neurol, 2, 482, 2003.
60.
ZhangG.L., ZhangX., WangX.M., and LiJ.P.Towards understanding the roles of heparan sulfate proteoglycans in Alzheimer's disease. Biomed Res Int, 2014, 516028, 2014.
61.
KehoeO., KaliaN., KingS., et al.Syndecan-3 is selectively pro-inflammatory in the joint and contributes to antigen-induced arthritis in mice. Arthritis Res Ther, 16, R148, 2014.
62.
ReizesO., LincecumJ., WangZ., et al.Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell, 106, 105, 2001.
63.
van HorssenJ., KleinnijenhuisJ., MaassC.N., et al.Accumulation of heparan sulfate proteoglycans in cerebellar senile plaques. Neurobiol Aging, 23, 537, 2002.
64.
FrancoR., and Cedazo-MinguezA.Successful therapies for Alzheimer's disease: why so many in animal models and none in humans? Front Pharmacol, 5, 146, 2014.
65.
YahataN., AsaiM., KitaokaS., et al.Anti-Abeta drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease. PLoS One, 6, e25788, 2011.
66.
BekrisL.M., YuC.E., BirdT.D., and TsuangD.W.Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol, 23, 213, 2010.
67.
RyazantsevaM., SkobelevaK., and KaznacheyevaE.Familial Alzheimer's disease-linked presenilin-1 mutation M146 V affects store-operated calcium entry: does gain look like loss? Biochimie, 95, 1506, 2013.
68.
OddoS., CaccamoA., ShepherdJ.D., et al.Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron, 39, 409, 2003.
69.
WangR., WangB., HeW., and ZhengH.Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology. J Biol Chem, 281, 15330, 2006.
70.
YamamizuK., IwasakiM., TakakuboH., et al.In vitro modeling of blood-brain barrier with human iPSC-derived endothelial cells, pericytes, neurons, and astrocytes via notch signaling. Stem Cell Reports, 8, 634, 2017.
71.
MaQ., CornelliU., HaninI., et al.Heparin oligosaccharides as potential therapeutic agents in senile dementia. Curr Pharm Des, 13, 1607, 2007.
72.
BergamaschiniL., RossiE., VerganiC., and De SimoniM.G.Alzheimer's disease: another target for heparin therapy. ScientificWorldJournal, 9, 891, 2009.
73.
ReynoldsM.R., SinghI., AzadT.D., et al.Heparan sulfate proteoglycans mediate Abeta-induced oxidative stress and hypercontractility in cultured vascular smooth muscle cells. Mol Neurodegener, 11, 9, 2016.
74.
TaylorD.R., WhitehouseI.J., and HooperN.M.Glypican-1 mediates both prion protein lipid raft association and disease isoform formation. PLoS Pathog, 5, e1000666, 2009.
75.
HolmesB.B., DeVosS.L., KfouryN., et al.Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A, 110, E3138, 2013.
76.
XiangY., TanakaY., PattersonB., et al.Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell, 21, 383, 2017.
77.
BireyF., AndersenJ., MakinsonC.D., et al.Assembly of functionally integrated human forebrain spheroids. Nature, 545, 54, 2017.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
